The fibroproliferative response of vascular smooth muscle cells (VSMCs) to injury is regulated by the combined action of both autocrine and paracrine growth factors. In addition, hormonal factors circulating in the blood plasma are important for cellular growth of VSMCs in tissue culture. In vivo, a similar paradigm seems to exist after vascular injury where growth factors that are locally produced act in conjunction with plasma factors to induce proliferation. It has been shown that hormonal factors dependent on the pituitary gland are involved in VSMC proliferation and migration after arterial injury. Injury-induced neointimal formation is inhibited in hypophysectomized rats. Indeed, atherosclerosis or restenosis may in part be mediated by a complex endocrine modulation. Hypophysectomy is a severe intervention and causes alterations in a number of hormonal factors; therefore, the exact mechanism(s) or factor(s) dependent on the pituitary gland is not known. In an attempt to further clarify this issue and pinpoint specific hormonal factors necessary for intimal thickening, we made rats specifically hypothyroid by dietary manipulations. Preliminary experiments show that rats fed thyroid suppressive diets (thiouracil-containing) exhibit a markedly diminished response to neointimal formation following balloon angioplasty. This blunted response was observed at 8, 14 and 21 days following vascular injury with the most significant inhibition occurring at 21 days. This also occurred in animals which, in addition to being rendered hypothyroid were made hyper-cholesterolemic. These observations suggest that the anti-proliferative effect of hypophysectomy on neointima formation is in part specifically mediated by a deficiency in thyroid hormone.